This invention relates to intravaginal drug delivery devices for the administration of testosterone and testosterone precursors to the human or animal female. The term xe2x80x98precursorxe2x80x99 is intended to embrace those compounds which can be readily converted in vivo into testosterone, in which the products of such conversion are clinically and toxicologically acceptable and which compounds possess certain physicochemical properties as defined hereinbelow. In particular, it relates to intravaginal drug delivery devices for the administration of testosterone or a testosterone precursor at a substantially zero order rate over a prolonged period to alleviate or prevent the symptoms associated with testosterone deficiency or, alternatively, to induce supratherapeutic levels.
The intravaginal drug delivery devices of the invention are particularly suitable for the alleviation or prevention of symptoms associated with testosterone deficiency either as a discrete treatment regimen or as an element of hormone replacement therapy in association with oestrogen or combined oestrogen/progestogen drug delivery devices. The clinical efficacy of testosterone replacement therapy, in association with exogenous oestrogen, has been reported from 1950 onwards [2]. The invention may, however, also have application to improve muscle mass and/or bone mass in patients with, for example, AIDS wasting syndrome or osteoporosis, respectively. In addition, the invention may have application as an antiproliferative agent for use against, for example, breast cancer, endometrial cancer, or endometriosis or, alternatively, to treat urogenital or vulval problems.
Plasma concentrations of testosterone in the normal, pre-menopausal, healthy human female are between 0.5 and 2.3 nM (0.15 to 0.65 ng per ml) with a mid-cycle peak [1]. Testosterone deficiency in the premenopausal human female may occur due to disease, oophorectomy, adrenalectomy or traumatic injury. In the postmenopausal female, testosterone deficiency arises primarily from a reduced adrenal output of androstenedione, which is peripherally converted to testosterone in vivo [1].
Testosterone may be administered by intramuscular injection as an oily solution or an aqueous suspension but, when administered by this route, testosterone is rapidly absorbed, metabolised and excreted. Testosterone esters are more hydrophobic than the free steroid and, consequently, are absorbed more slowly than testosterone from the intramuscular route. However, no rate-controlling mechanism is provided and intramuscular injection of a testosterone ester cannot, therefore, provide a substantially zero order pattern of release.
Following oral administration, testosterone or testosterone derivatives are readily absorbed but have poor efficacy because of considerable first-pass hepatic metabolism. Prolonged delivery for at least three weeks in a substantially zero order pattern of release cannot be achieved by the oral route.
GB-B-2 185 187 and GB-B-2 161 073 teach that testosterone may be absorbed across human scrotal skin from a flexible patch over, preferably, 24 hours. A matrix (or non-rate controlled) system for transdermal testosterone delivery to the human female is also known [3]. This system delivers about 1000 xcexcg of testosterone per day, yielding mean circulating plasma testosterone levels of 4-6 nM. Transdermal administration avoids first-pass hepatic metabolism. However, the physical size of transdermal drug delivery systems is such that a new device must be used every few days. This can lead co fluctuations in circulating serum testosterone levels. Furthermore, frequent device replacement is inconvenient and has possible compliance problems for the patient. Although transdermal delivery systems that can maintain substantially constant delivery are known, it is not possible to maintain a substantially zero order delivery for at least three weeks by this route.
Subcutaneous implantation (50 or 100 mg) of testosterone-loaded pellets provides therapy extending to several months and is therefore advantageous in respect of both patient compliance and convenience. However, subcutaneous implants have a number of disadvantages. Specifically, a surgical procedure is required for both insertion and removal of the pellets. In addition, infection, pain and swelling can arise at the insertion site. Furthermore, due to physical size limitations of such systems, it is not possible to make testosterone implants that can deliver the hormone in a substantially zero order pattern over a prolonged period of at least three weeks.
It might be expected that many of the problems associated with long-term testosterone delivery in the human or animal female could be overcome by intravaginal administration of testosterone or testosterone precursors. The vaginal route avoids undesirable first-pass hepatic metabolism. Delivery of testosterone or a testosterone precursor by this route would be expected to be analogous to the natural secretion of testosterone per se into systemic circulation. To achieve substantially zero order pattern of testosterone release, sustained over a period of at least three weeks in order to enhance both patient compliance and convenience, an intravaginal drug delivery device might be expected to be the most suitable drug delivery device. However, there is no teaching of such a device to deliver testosterone at all.
Three basic designs of intravaginal ring are possible, though additional design variations do exist:
(a) The homogeneous or matrix ring, in which the drug is distributed in a polymer matrix. This design is associated with an initial high release of drug, producing a non-physiological circulating plasma level, followed by a decline in the drug release rate as the outer portions of the ring are depleted of drug. Consequently, this ring design cannot deliver the desired substantially constant (or zero order) drug release over a sustained period.
(b) The shell design, in which the drug is contained in a hollow annulus between a drug-free central member and a drug-free sheath or rate-controlling membrane. With this design, burst effects are reduced compared to the homogeneous ring. However, the drug reservoir is physically limited in size and the relative diameters of drug-free central member, hollow drug-containing annulus (polymer matrix) and rate-controlling sheath are such that, where comparatively high daily drug release rates are required, as in supratherapeutic testosterone therapy (e.g. testosterone replacement), this design cannot sustain drug delivery for the desired period of at least three weeks. This design can, of course, sustain drug delivery over at least three weeks, when lower daily drug release rates are required for other indications.
(c) The core design, in which the drug is contained in a core, surrounded by a rate-controlling, drug-free sheath. In this design, high drug loadings are possible and the relative diameters of core and sheath are such that a higher drug release rate can be achieved compared to the shell design. Burst release of drug is reduced compared to the homogeneous ring. Substantially zero order release can be achieved and such release can be sustained for at least three weeks and up to several months due to the higher drug loading possible with this design.
Although intravaginal drug delivery devices containing oestrogens and/or progestogens are long known in the art, there is no teaching in the literature of an intravaginal drug delivery device containing testosterone for any purpose. This is despite intravaginal drug delivery devices being well-known to those skilled in the art and the clinical benefits of testosterone administration being known for many years.
Prejudice against the incorporation of testosterone or a testosterone precursor in an intravaginal drug delivery device in the human or animal female may be at least partially explained by:
(a) The comparatively low apparent permeability coefficient of testosterone across vaginal epithelium, normalised with respect to that of methanol [4]. The apparent permeability coefficient is, in effect, a measure of the ability of a drug to be absorbed from the hydrodynamic layer in the vaginal lumen across the vaginal epithelium into the serosal compartment. The low apparent permeability coefficient of testosterone (0.29) compared to that of, for example, progesterone (0.93) and oestrone (1.00), teaches that a relatively high concentration gradient will be required across the vaginal barrier membrane in order to deliver testosterone into systemic circulation at clinically useful levels [4];
(b) The relatively low aqueous solubility of testosterone itselfxe2x80x9425 xcexcg/ml [4], and the even lower aqueous solubility of the more lipophilic testosterone ester precursorsxe2x80x94it would be considered, therefore, to be unlikely that a high enough concentration gradient could be achieved, to deliver clinically useful levels of testosterone into systemic circulation; and
(c) A lack of knowledge regarding the daily dosage of testosterone to be delivered in a substantially zero order manner over a prolonged period of at least three weeks such that the circulating systemic levels of testosterone are within the desired range.
Accordingly, it is a novel aspect of the present invention to provide an intravaginal shell or core drug delivery device comprising testosterone or a testosterone precursor as defined hereinbelow in a polymer matrix, surrounded by a sheath. The sheath may be formed from the same material as the polymer matrix, or from other suitable, compatible material known in the art. Said device is capable of releasing testosterone or testosterone precursor in a substantially zero order pattern on a daily basis for a period of at least three weeks.
Said testosterone precursors for human use must possess physicochemical properties such that they can be delivered from an intravaginal drug delivery device at a daily rate that will restore circulating testosterone levels to within the normal physiological range found in the healthy, human, pre-menopausal female (therapeutic levels) or, alternatively, induce supratherapeutic levels. By way of example only, the term xe2x80x9ctestosterone precursorsxe2x80x9d includes testosterone esters such as 17 xcex2-alkanoyl esters of testosterone, preferably C1xe2x88x9215 saturated or unsaturated straight or branched chain alkanoyl esters, more preferably, testosterone-17-acetate and testosterone-17-propionate.
Whilst the intravaginal device can have any shape and be of any dimensions compatible both with intravaginal administration to the human or animal female and with the requirements imposed by drug delivery kinetics, a particularly preferred device according to the present invention is an elastomeric intravaginal ring. A bullet-shaped pessary is also preferred.
Preferably, daily in vitro release rates of at least 100 xcexcg testosterone, or of a testosterone precursor equivalent to at least 100 xcexcg testosterone per se (testosterone equivalent), can be sustained for up to 12 months in a substantially zero order pattern, said daily release rates resulting in the desired therapeutic or supratherapeutic circulating levels of testosterone.
More preferably, the intravaginal drug delivery device is capable of delivering testosterone in a substantially zero order pattern for a period of at least three weeks and up to 12 months at an in vitro daily release rate of at least 100 xcexcg.
Advantageously, the intravaginal drug delivery device may contain other compatible pharmaceutically active agents. Such pharmaceutically active agents include, but are not limited to, natural or synthetic steroids, for example, oestrogens, progesterones and adrenocortical hormones.
According to a second aspect of the invention there is provided a method of manufacturing an intravaginal shell or core drug delivery device having an outer sheath and a polymer matrix containing testosterone or a testosterone precursor as defined hereinbefore for testosterone administration to the human or animal female. Said method comprises the steps of combining testosterone or a testosterone Precursor and a polymer to form the polymer matrix; and surrounding the polymer matrix with a sheath, whereby the relative amounts of the respective polymer matrix and sheath are chosen, and the geometry of the drug delivery device components selected, to provide a daily substantially zero order pattern release of at least 100 xcexcg of either testosterone per se or testosterone equivalent for at least three weeks.
The intravaginal drug delivery device may be constructed from one or more biocompatible elastomers compatible with testosterone or the testosterone precursor. Where the elastomer is chosen from the room-temperature vulcanising type of hydroxyl-terminated organopolysiloxanes, suitable cross-linking agents and curing catalysts known in the art may be required. Dimethylpolysiloxane compositions may also be used as the elastomeric component of the intravaginal drug delivery device of the invention.
The geometry of the intravaginal drug delivery device may be chosen such that the daily substantially zero order pattern release of testosterone or a testosterone precursor can be varied up to at least 5000 xcexcg of testosterone or testosterone equivalent, preferably in the range from 100 to 1500 xcexcg of testosterone or testosterone equivalent. The term xe2x80x9cgeometryxe2x80x9d encompasses the overall dimensions of the device, as well as, the relative dimensions of the drug/polymer matrix and the sheath. When the device is a ring, the term xe2x80x9cgeometryxe2x80x9d encompasses the overall diameter of the ring; the cross-sectional diameter of the ring; the ratio of the polymer matrix (core or annulus) diameter to the diameter of the whole device in cross-section; and the length of the polymer matrix (core or annulus).
The percentage loading of testosterone or testosterone precursor contained in the polymer matrix can vary from between 1 to 90% w/w. The only importance of the drug loading in a shell or core device design is to ensure that there is sufficient drug present at all times to allow a substantially zero order pattern of drug release to be maintained throughout the required period of sustained drug release. Thus, to ensure maintenance of the substantially zero order drug release pattern throughout the lifetime of the device, the necessary drug loading must be sufficiently in excess of the total drug required to be delivered over the defined sustained-release period.
The intravaginal drug delivery device according to the present invention, as will be exemplified hereinafter, achieves a sufficiently high aqueous concentration of testosterone or testosterone precursor to be expected to promote absorption of testosterone or testosterone precursor through the vaginal epithelial membrane by passive diffusion along a concentration gradient, despite the already mentioned low aqueous solubility of said compounds and despite the already mentioned low apparent permeability coefficient for testosterone.
Several embodiments of the invention will now be described by reference to the General Method of Manufacture of an intravaginal drug delivery device according to the invention and will be exemplified by reference to the following Examples. It should be understood that these examples are disclosed solely by way of further illustrating the invention and should not be taken in any way to limit the scope of said invention. Thus, for instance, it will be obvious to those skilled in the art that the technique of injection moulding referred to therein may be replaced in whole or in part by other manufacturing techniques that will produce the same end product, for example, the technique of extrusion.
General Method of Manufacture
An elastomer mix is prepared by blending 97 parts by weight of a hydrophobic elastomeric polymer containing about 25% w/w diatomaceous earth as the filler with 2.5 parts by weight of a cross-linking agent, n-propylorthosilicate. A suitable hydrophobic elastomeric polymer is stannous octoate-cured polydimethylsiloxane polymer, two suitable examples of which are those known as Dow Corning QCF7 3099 and Nusil Med 7.6382.
An active mix is formed by blending 85 parts by weight of the elastomer mix, 5 parts by weight of barium sulphate and 10 parts by weight of testosterone or testosterone precursor.
The core of a core intravaginal drug delivery device of the invention is produced by mixing 200 parts by weight of the active mix with 1 part by weight of an activating catalyst, stannous octoate. The resultant core mix is injected into a core mould and cured at 80xc2x0 C. for 2 minutes. The mould is then opened and the core is removed and trimmed.
The sheath mix is formed by mixing 200 parts by weight of the elastomer mix with 1 part by weight of an activating catalyst, for example, stannous octoate. An intravaginal drug delivery device in the form of a half ring is produced by injecting the sheath mix into a half ring mould containing a previously prepared core and then curing at 80xc2x0 C. for 2 minutes. The mould is then opened, following which the half ring is removed and trimmed.
An intravaginal drug delivery device in the form of a complete ring is produced by injecting the sheath mix into a full ring mould containing the previously prepared half ring and then curing at 80xc2x0 C. for 2 minutes. The mould is then opened, following which the full ring is removed and trimmed.
With a drug loading of 10% or less, it is possible to hand inject the core mix into the mould. However, as the drug loading is increased, the viscosity of the core mix increases and it becomes necessary to extrude the core mix into the mould.
The geometric characteristics of the ring can be varied as required by the use of appropriately sized moulds or extrusion nozzles, as will be obvious to those skilled in the art.
It will be appreciated that a shell intravaginal drug delivery device would be analogously prepared, although not specifically described herein.